Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC/C-CDH1 pathway in colorectal cancer cells

Background: Metabolic reprogramming is a hallmark of cancer, alteration of nucleotide metabolism of hepatocellular carcinoma (HCC) is not well-understood. MYBL2 regulates cell cycle progression and hepatocarcinogenesis, its role in metabolic regulation remains elusive.Patients and methods: Copy number, mRNA and protein level of MYBL2 and IMPDH1 were analyzed in HCC, and correlated with patient survival. Chromatin Immunoprecipitation sequencing (Chip-seq) and Chromatin Immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) were used to explore the relationship between MYBL2 and IMPDH1. Metabolomics were used to analyze how MYBL2 affected purine metabolism. The regulating effect of MYBL2 in HCC was further validated in vivo using xenograft models.Results: The Results showed that copy-number alterations of MYBL2 occur in about 10% of human HCC. Expression of MYBL2, IMPDH1, or combination of both were significantly upregulated and associated with poor prognosis in HCC. Correlation, ChIP-seq and ChIP-qPCR analysis revealed that MYBL2 activates transcription of IMPDH1, while knock-out of MYBL2 retarded IMPDH1 expression and inhibited proliferation of HCC cells. Metabolomic analysis post knocking-out of MYBL2 demonstrated that it was essential in de novo purine synthesis, especially guanine nucleotides. In vivo analysis using xenograft tumors also revealed MYBL2 regulated purine synthesis by regulating IMPDH1, and thus, influencing tumor progression.Conclusion: MYBL2 is a key regulator of purine synthesis and promotes HCC progression by transcriptionally activating IMPDH1, it could be a potential candidate for targeted therapy for HCC.

Small cell lung cancer (SCLC) responds poorly to immunotherapy. This study investigates how glycolytic reprogramming drives immune evasion in SCLC by epigenetically suppressing MHC-I mediated antigen presentation. Bioinformatic and murine model studies confirmed SCLC with high ASCL1 expression (SCLC-A) as an immunologically "cold" subtype, exhibiting elevated glycolytic activity that was inversely correlated with profoundly suppressed MHC-I pathway activity. High LDHA expression was associated with advanced disease stage and shorter overall survival in patients. In vitro and in vivo studies demonstrated that LDHA knockdown or its pharmacological inhibition restored the expression of MHC-I (H2Db/H2Kb; HLA-ABC) and β2-microglobulin (B2M). This promoted antitumor immunity, increasing CD4⁺ and CD8⁺ T cell infiltration and inhibiting tumor growth. These effects were reversed by sodium lactate, confirming lactate as the key metabolite. Mechanistically, LDHA-derived lactate promoted histone H4K5 lactylation (H4K5la) via the acyltransferase P300. This modification enriched at the promoters of the PRC2 core subunits EZH2 and EED, enhancing their transcription and thus PRC2-mediated silencing of MHC-I. The restoration of MHC-I following LDHA loss was mediated by a parallel H4K5la-PRC2 regulatory axis independent of the canonical NLRC5 pathway. Combination therapy with LDHA inhibitor FX11 and anti-PD-1 antibody synergistically inhibited tumor growth and enhanced immune activation with a favorable safety profile. Our work uncovers the LDHA-H4K5la-PRC2 axis as a novel metabolic-epigenetic pathway that suppresses antigen presentation in SCLC-A. Targeting this axis with an LDHA inhibitor effectively sensitizes SCLC to anti-PD-1 therapy, representing a promising strategy to overcome immunotherapy resistance.

Background: Metabolic reprogramming is a hallmark of cancer, alteration of nucleotide metabolism of hepatocellular carcinoma (HCC) is not well-understood. MYBL2 regulates cell cycle progression and hepatocarcinogenesis, its role in metabolic regulation remains elusive. Patients and methods: Copy number, mRNA and protein level of MYBL2 and IMPDH1 were analyzed in HCC, and correlated with patient survival. Chromatin Immunoprecipitation sequence (Chip-seq) and Chromatin Immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) were used to explore the relationship between MYBL2 and IMPDH1. Metabolomics were used to analyze how MYBL2 affected purine metabolism. The regulating effect of MYBL2 in HCC was further validated in vivo using xenograft models. Results: The Results showed that copy-number alterations of MYBL2 occur in about 10% of human HCC. Expression of MYBL2, IMPDH1, or combination of both were significantly upregulated and associated with poor prognosis in HCC. Correlation, ChIP-seq and ChIP-qPCR analysis revealed that MYBL2 activates transcription of IMPDH1, while knock-out of MYBL2 retarded IMPDH1 expression and inhibited proliferation of HCC cells. Metabolomic analysis post knocking-out of MYBL2 demonstrated that it was essential in de novo purine synthesis, especially guanine nucleotides. In vivo analysis using xenograft tumors also revealed MYBL2 regulated purine synthesis by regulating IMPDH1, and thus, influencing tumor progression. Conclusion: MYBL2 is a key regulator of purine synthesis and promotes HCC progression by transcriptionally activating IMPDH1, it could be a potential candidate for targeted therapy for HCC.

Tinnitus is a prevalent and distressing medical symptom, and no effective pharmacological treatment currently exists. Despite significant advances, tinnitus remains a scientific enigma. To explore the molecular underpinnings of tinnitus, we developed a noise-induced tinnitus model in mice and utilized metabolomics to identify key differences in metabolic pathways. Our results revealed that oxidative stress-related pathways, including glutathione (GSH) metabolism, were significantly enriched in the auditory cortex of mice exhibiting tinnitus-like behavior. To further explore the role of oxidative stress, we examined the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) in tinnitus by conducting experiments in Nrf2 knockout (Nrf2-KO) mice. While Nrf2-deficient mice did not develop spontaneous tinnitus or hearing loss, they displayed increased susceptibility to prolonged tinnitus-like behavior after noise exposure. This was accompanied by heightened microglial activation, neuroinflammation, and significant alterations in gut microbiota composition, including greater diversity and dysbiosis. Our findings highlight a novel mechanism underlying tinnitus, emphasizing the role of oxidative stress in the auditory cortex and its connection to noise-induced tinnitus. The deficiency of Nrf2 in mice increases their susceptibility to tinnitus, suggesting that Nrf2 may serve as a promising therapeutic target for preventing noise-induced tinnitus.